Parry DA et al. (2013), SAMS, a syndrome of short stature, auditory-can...

XB-ART-47686

Am J Hum Genet 2013 Dec 05;936:1135-42. doi: 10.1016/j.ajhg.2013.10.027.

Show Gene links Show Anatomy links

SAMS, a syndrome of short stature, auditory-canal atresia, mandibular hypoplasia, and skeletal abnormalities is a unique neurocristopathy caused by mutations in Goosecoid.

Parry DA , Logan CV , Stegmann AP , Abdelhamed ZA , Calder A , Khan S , Bonthron DT , Clowes V , Sheridan E , Ghali N , Chudley AE , Dobbie A , Stumpel CT , Johnson CA .

???displayArticle.abstract???
Short stature, auditory canal atresia, mandibular hypoplasia, and skeletal abnormalities (SAMS) has been reported previously to be a rare, autosomal-recessive developmental disorder with other, unique rhizomelic skeletal anomalies. These include bilateral humeral hypoplasia, humeroscapular synostosis, pelvic abnormalities, and proximal defects of the femora. To identify the genetic basis of SAMS, we used molecular karyotyping and whole-exome sequencing (WES) to study small, unrelated families. Filtering of variants from the WES data included segregation analysis followed by comparison of in-house exomes. We identified a homozygous 306 kb microdeletion and homozygous predicted null mutations of GSC, encoding Goosecoid homeobox protein, a paired-like homeodomain transcription factor. This confirms that SAMS is a human malformation syndrome resulting from GSC mutations. Previously, Goosecoid has been shown to be a determinant at the Xenopus gastrula organizer region and a segment-polarity determinant in Drosophila. In the present report, we present data on Goosecoid protein localization in staged mouse embryos. These data and the SAMS clinical phenotype both suggest that Goosecoid is a downstream effector of the regulatory networks that define neural-crest cell-fate specification and subsequent mesoderm cell lineages in mammals, particularly during shoulder and hip formation. Our findings confirm that Goosecoid has an essential role in human craniofacial and joint development and suggest that Goosecoid is an essential regulator of mesodermal patterning in mammals and that it has specific functions in neural crest cell derivatives.

???displayArticle.pubmedLink??? 24290375
???displayArticle.pmcLink??? PMC3853132
???displayArticle.link??? Am J Hum Genet

Species referenced: Xenopus
Genes referenced: gsc hhip pax3 pax6
GO keywords: embryo development

???attribute.lit??? ???displayArticles.show???

	Figure 1 Clinical Features of SAMS in Individual C. (A–C) At the age of 1 month, individual C presented with malar hypoplasia, severe micrognathia, scaphocephaly with a prominent forehead, downward-slanting palpebral fissures, and rhizomelic shortening of the upper limbs (A). Rudimentary pinnae with bilateral atresia of the (B) right and (C) left external auditory canals with small preauricular tags (arrowheads) can be seen. (D) Pedigree of individual C (arrow) and unaffected family members. (E and F) Left humeroscapular synostosis (E, arrowhead) but normal right shoulder joint (F), with bilateral shortening of the humeri and flaring of the distal metaphyses. (G) Immature ossification of the pelvis, with a flattened acetabulum and bilaterally dislocated hips, and absence of ossification of the pubic rami. (H) Fixed talipes equinovarus of the right foot.
	Figure 2 Homozygous-Null Mutations and Microdeletion of GSC Cause SAMS. A) fancyGENE representation9 of human GSC and homozygous point mutations identified in SAMS individuals A, C, and D. The homeobox domain is shown in green. Mutations are marked on the gene in red, and corresponding electropherograms are shown in the top panels, as indicated (red arrows). Wild-type normal sequence is shown below for comparison. (B) Affymetrix CytoScan HD Microarray SNP genotyping of individual B for chromosome 14. The top track identifies a copy-number segment (brown, indicated by a red arrowhead). Other tracks show the log2 ratio signal intensity (blue), genes (pink), and stretches of contiguous loss of heterozygosity (LoH; purple) consistent with identity-by-descent from the consanguineous parents. (C) Array result for individual B of chromosomal region 14q32.13 shows a 306 kb copy-number segment loss arr 14q32.13(95,204,793-95,511,597)x0 (brown, indicated by a red arrowhead) with a copy-number state (light purple) of CN = 0, indicating a homozygous deletion. The Goosecoid gene (GSC) is indicated on the gene track (pink arrowhead), and the physical location in kb is shown at the bottom.
	Figure 3 Goosecoid Colocalizes with Pax3 in Neural-Crest Derivatives and the Developing Pelvis. (A) Mouse embryonic midline sagittal and horizontal sections showing Goosecoid (green) and Pax3 (red) colocalization in neural-crest-tissue derivatives in the frontonasal prominence (fnp) and the first branchial arch (BA1) and bony attachment points in the embryonic shoulder joint (arrowheads). Scale bars represent 20 μm. Abbreviations are as follows: gc, glenoid cavity; and hu, humerus. (B) Goosecoid and Pax3 colocalization in the developing pubic bone for a midline sagittal section of an E14.5 mouse embryo. The scale bar represents 20 μm. A magnified inset (bottom) is indicated by a white frame.
	Figure S1: Clinical features of SAMS in individual B H (A-B) Individual B at age of 19 years, presenting with micrognathia, asymmetrical facial features, auditory canal atresia, (C-E) shortening of both humeri with bilateral scapulo-humeral synostosis, lumbar hyperlordosis and central dislocation of both hips. (F) Left and (G-H) right foot after repeat clubfeet surgery. Walking is only possible with the use of orthopaedic shoes.
	Figure S2: Goosecoid localization in mouse embryonic tissues Immunofluoresence (IF) confocal microscopy of mouse embryonic sections for the indicated tissues stained for Goosecoid (green) and nuclei (DAPI, in blue). (A) E11.5 distal hindlimb stained following peptide competition (left panel) and with anti-Goosecoid only (right panel) to confirm the specificity of the antibody reagent. Note the nuclear localization of Goosecoid in connective tissue by the fibula. Para-sagittal section; scale bar = 50μm. (B) Specific, high levels of Goosecoid localization in E10.5 hindlimb mesodermal condensation (left panel), including the probable femoral head (arrowhead). Goosecoid localization also surrounded the neural tube (right panel; nt) and was in the post-otic neural crest cells (PONC) surrounding the otic vesicle (ov; arrowhead) but not in neuronal tissues; 4V, fourth ventricle. Para-sagittal and horizontal sections, respectively; scale bars = 100 and 70 μm, as indicated. (C) High levels of Goosecoid expression (arrowhead) in E11.5 mouse embryonic mandibular process of the first branchial arch (BA1), anterior and hind limb buds (arrowhead) and developing ribs. Midline and para-sagittal sections, scale bar = 20μm for all panels. (D) Goosecoid expression in E12.5 embryonic connective tissue but not bone primordia of hindlimb and forelimb, muscles and connective tissue of the shoulder joint, and the mandibular primordium. Midline and para-sagittal sections, scale bars = 20μm.
	Figure S3: Goosecoid co-localizes with Pax3 in neural crest derivatives and bone primordia ns inc rp mnc drg IF microscopy for mouse E12.5 embryonic horizontal and para-sagittal sections for the indicated tissues stained for Goosecoid (green), Pax3 (red) and nuclei (DAPI, in blue). Goosecoid is co-expressed with Pax3 in neural crest tissue derivatives in post-otic cranial neural crest cells (PONC), nasal cavity, dorsal root ganglia (drg) and rib primordia (rp), and hindlimb bud. Abbreviations: inc, inferior nasal concha; mnc, middle nasal concha; ns, nasal septum.

References [+] :

Abdelhamed, Variable expressivity of ciliopathy neurological phenotypes that encompass Meckel-Gruber syndrome and Joubert syndrome is caused by complex de-regulated ciliogenesis, Shh and Wnt signalling defects. 2013, Pubmed